Technical Field
Provided herein are methods of treating schizophrenia, schizoaffective disorder, bipolar disease, major depressive disorder and other conditions commonly treated with antipsychotic medication by administering to a subject in need thereof a pharmaceutical composition comprising an antipsychotic compound and a VMAT2 inhibitor.
Description of the Related Art
Schizophrenia affects approximately 1% of the adult population and reduces life expectancy by an average of 20 to 25 years through the impact of the disorder on self-care and physical health, as well as through suicide. At the present time the etiological mechanisms underlying schizophrenia are poorly understood. Schizophrenia is diagnosed clinically, based on characteristic symptoms of psychosis, disorganization and so called ‘negative’ symptoms (representing a reduced range of emotional expression, reduced production of speech and a lack of volition/motivation); duration of illness; impaired functioning; and the exclusion of other disorders such as autism and bipolar disorder. For clinicians, identifying which psychotic patients have schizophrenia requires clinical acumen and familiarity with the DSM-IV or ICD-10 diagnostic manuals (see, e.g., Corvin, BMC Biol. 2011; 9: 77).
Antipsychotic drug therapy is a pillar in the treatment of schizophrenia. These antipsychotic drugs, also known as neuroleptics, generally cause a reduction of the ‘positive’ symptoms of schizophrenia, namely psychosis, thought disorders, and disorganized behavior. Antipsychotics generally have a lesser influence on cognition and on the ‘negative’ symptoms of the disease, which include lack of motivation and emotion, social withdrawal, lack of interest in everyday activities, and the reduced ability to plan or carry out activities.
First generation or “typical” antipsychotics have been used for over 50 years in the treatment of schizophrenia and other psychotic disorders. The first marketed antipsychotic was chlorpromazine; other typical antipsychotics include fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, sulpiride, thioridazine, and trifluoperazine. These typical antipsychotics all gain their primary efficacy through D2 dopamine receptor antagonism and have a propensity to cause movement disorders including parkinsonism (tremor, rigidity, bradykinesia and gait instability) as well as dystonia, dyskinesia (e.g., tardive dyskinesia), and akathisia.
Second generation or “atypical” antipsychotics were developed, and these drugs possess a lower risk of causing TD and related movement disorders with chronic administration. These drugs include aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. These atypical antipsychotics all exert their primary efficacy through D2 dopamine receptor antagonism with additional effects on receptors for other neurotransmitters. These atypical antipsychotics are associated with metabolic side effects sufficient to affect life expectancy. These side effects include a propensity to induce weight gain, as well as related metabolic disturbances such as hypertriglyceridemia and hyperglycemia. Clozapine appears to be the most effective as treatment for severe mental illness, but it has additional serious medical side effects, including a significant incidence of agranulocytosis that requires frequent monitoring of patients' white blood counts as a requirement for using the drug.
In addition to treatment of schizophrenia and schizoaffective disorder, certain antipsychotic medications have been approved as treatments of bipolar disorder, major depressive disorder (MDD), and autism spectrum disorders. Off-label use is prevalent, particularly of atypicals, which are used for the treatment of various conditions including anxiety, attention-deficit hyperactivity disorder (ADHD), dementia, depression, insomnia, obsessive-compulsive disorder (OCD), post-traumatic stress disorder, substance abuse, and Tourette's syndrome.
Because the side effects associated with administration of antipsychotic medications can significantly impact a patient's health and well-being, alternatives to the current therapies are needed.